The role of the endogenous opioid system in social motivation and cognition in the valproic acid model of social impairment

Positive social interactions and successful relationships are important for physical and mental health, and have been shown to elicit beneficial effects on multiple physiological systems and bodily function. Impairments in social responding are characteristic of multiple neurodevelopmental and psychiatric disorders such as depression, schizophrenia, bipolar disorder and autism. Although accumulating evidence describes the underlying neurobiology of social responding, less is known about the neurobiological underpinnings of social behaviour in neurodevelopmental and psychiatric illnesses. As such, clinically relevant models mimicking the social behavioural deficits associated with these conditions have proven an invaluable tool with which to examine how the molecular mechanisms mediating these behavioural alterations. The endogenous opioid system has been long-established to mediate and modulate social responding however such effects have primarily been examined in direct social interaction test. The data presented in this thesis add to this knowledge and demonstrate for the first time that the effects of opioid receptor agonism and antagonism on social responding are age (adolescent vs adult rats) and context (direct social interaction vs 3-chamber test) dependent. It is well-established that prenatal exposure to the anti-epileptic valproic acid induces lasting impairments in social play behaviour, social interaction and social novelty preference. The present findings demonstrate for the first time that rats prenatally exposed to VPA exhibit numerous alterations in the expression of endogenous opioid receptors and pre-pro-peptides in various brain regions involved in social motivation and cognition in both adolescence and adulthood, when compared to age matched saline-exposed counterparts. Furthermore, pharmacological modulation of each of the opioid receptors, MOP, KOP and DOP, alone and in combination, leads to differential effects on social motivation and cognition in rats prenatally exposed to VPA compared to saline exposed counterparts. In particular it was noted that MOP agonism reduced social motivation and cognition in saline-exposed rats, while it increased social motivation in VPA-exposed rats. These effects were not due alterations in plasma or brain levels or MOP receptor occupancy of the agonists but were associated with changes in the expression of immediate early gene expression in discrete brain regions that modulate social motivation and cognition. In comparison KOP antagonism was associated with increased social motivation but impaired social cognition in saline-exposed rats, while KOP antagonism restored the previously impaired social novelty preference behaviour in VPA-exposed rats. These differential effects were found to be associated with alterations in the induction of immediate early gene expression and expression of opioid receptors and pre-pro-peptides in discrete brain regions. DOP agonism alone did not alter social responding of either saline or VPA exposed rats. Although KOP antagonism in combination with DOP or MOP agonism elicit some differential effects on social responding in saline vs VAP exposed rats, none of these combinations increased social responding in VPA exposed animals. Thus, the data herein describe alterations in the expression and functionality of the endogenous opioid system in the VPA model, effects which may at least in part underlie the social motivational and cognitive impairments observed in the model. These data provide important insights into the role of the opioid system in mediating and modulating social responding in a clinically relevant developmental model, and thus may have implications in understanding social deficits and withdrawal associated with neurodevelopmental and psychiatric disorders.

Funder

Science Foundation Ireland
Alkermes Inc.

Publisher

NUI Galway

Rights

Attribution-NonCommercial-NoDerivs 3.0 Ireland

cbn

Collections

University of Galway Theses (PhD Theses)